Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitoph-agy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control dis-rupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen spe-cies production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chlo-roquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-a overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy.

Automated summary

Patients with Leber's hereditary optic neuropathy (LHON) exhibit sustained abnormal autophagy and compartment-specific mitophagy activity, disrupting mitochondrial homeostasis and leading to defective bioenergetics and excessive reactive oxygen species production. Modulating autophagy and mitochondrial biogenesis can counteract this pathological mechanism.